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Introduction: This paper describes the peculiarities of the plasma-derived medicinal product (PDMP) market and illustrates the results of a review of the literature on policies aimed at counteracting the shortage of PDMPs.Characteristics of PDMPs: Plasma is primarily used for the industrial production of blood products (80%). The demand for PDMPs, particularly immunoglobulins (IGs), is increasing. However, the production of PDMPs is complex, long (7–12 months), and expensive, accounting, according to US estimates, for 57% of the total costs of PDMPs compared to 14% for small molecules.PDMP market: Unexpected increases in clinical need cannot be addressed in the short term. Once the demand for some diseases is satisfied, the collection and fractionation of plasma will only be used to supply some specific patients. Hence, the full weight of the marginal costs, which remain constant, are borne by a few products. According to last liter economics, the industry stops producing when the marginal revenue equals the marginal cost, thereby reducing the convenience of producing the most commonly used PDMPs (albumin and IG). The imbalance between the demand and supply of PDMPs was exacerbated by the COVID-19 pandemic, which further increased the cost of plasma collection.Shortage issue and possible solutions: Policies to counteract this imbalance have also been discussed. If the demand is inappropriate, it should be reduced. If the demand is appropriate and supply cannot be increased, the demand should be prioritized for patients for whom PDMPs are the only available treatment. If the shortage depends on insufficient supply and technical and allocative efficiency, both production and supply should be improved, together with incentives for all stakeholders involved in the PDMP market to increase the sustainability of production/supply. The paper is focused on this second issue, that is supply-driven unbalance

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Shortage of plasma-derivedmedicinal products: what is next?narrative literature review on itscauses and counteracting policiesin ItalyMatteo Bolcato1† and Claudio Jommi2*†1Department of Neuroscience, University of Padova, Padova, Italy, 2Department of PharmaceuticalSciences, Università del Piemonte Orientale, Novara, ItalyIntroduction: This paper describes the peculiarities of the plasma-derivedmedicinal product (PDMP) market and illustrates the results of a review of theliterature on policies aimed at counteracting the shortage of PDMPs.Characteristics of PDMPs: Plasma is primarily used for the industrial productionof blood products (80%). The demand for PDMPs, particularly immunoglobulins(IGs), is increasing. However, the production of PDMPs is complex, long(7–12 months), and expensive, accounting, according to US estimates, for 57%of the total costs of PDMPs compared to 14% for small molecules.PDMPmarket: Unexpected increases in clinical need cannot be addressed in theshort term. Once the demand for some diseases is satisfied, the collection andfractionation of plasma will only be used to supply some specific patients. Hence,the full weight of the marginal costs, which remain constant, are borne by a fewproducts. According to last liter economics, the industry stops producing whenthe marginal revenue equals the marginal cost, thereby reducing theconvenience of producing the most commonly used PDMPs (albumin and IG).The imbalance between the demand and supply of PDMPs was exacerbated bythe COVID-19 pandemic, which further increased the cost of plasma collection.Shortage issue and possible solutions: Policies to counteract this imbalancehave also been discussed. If the demand is inappropriate, it should be reduced. Ifthe demand is appropriate and supply cannot be increased, the demand shouldbe prioritized for patients for whom PDMPs are the only available treatment. If theshortage depends on insufficient supply and technical and allocative efficiency,both production and supply should be improved, together with incentives for allstakeholders involved in the PDMP market to increase the sustainability ofproduction/supply. The paper is focused on this second issue, that is supply-driven unbalance.KEYWORDSplasma-derived medicinal products, market, supply, demand, policy, shortageOPEN ACCESSEDITED BYViviana Giannuzzi,Fondazione per la Ricerca FarmacologicaGianni Benzi onlus, ItalyREVIEWED BYAikaterini Alexaki,Centre Hospitalier Universitaire Vaudois(CHUV), SwitzerlandFedele Bonifazi,Fondazione per la ricerca farmacologica GianniBenzi onlus, Italy*CORRESPONDENCEClaudio Jommi,claudio.jommi@uniupo.it†These authors have contributed equally tothis workRECEIVED 24 January 2024ACCEPTED 05 April 2024PUBLISHED 06 May 2024CITATIONBolcato M and Jommi C (2024), Shortage ofplasma-derived medicinal products: what isnext? narrative literature review on its causesand counteracting policies in Italy.Front. Pharmacol. 15:1375891.doi: 10.3389/fphar.2024.1375891COPYRIGHT© 2024 Bolcato and Jommi. This is an open-access article distributed under the terms of theCreative Commons Attribution License (CC BY).The use, distribution or reproduction in otherforums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication in thisjournal is cited, in accordance with acceptedacademic practice. No use, distribution orreproduction is permitted which does notcomply with these terms.Frontiers in Pharmacology frontiersin.org01TYPE ReviewPUBLISHED 06 May 2024DOI 10.3389/fphar.2024.1375891IntroductionThis study explores the characteristics of the plasma-derivedmedicinal product (PDMP) market, reasons for the shortage ofPDMPs, and policies aimed at addressing shortages. We conducteda literature review using Embase, which is more appropriate foreconomic topics related to health and healthcare than otherdatabases. The key words used referred in general to PDMPs(“plasma-derive*” “plasma derived medicinal product” “supply*”“demand*” “industr*” “market*”, “patient blood management”, withexclusion of “clinical study”) and more specifically to immunoglobulins(IG), that were more affected by market shortages (“immunoglobulin”“self-sufficienc*” “shortage*” “supply*” “demand*” “industr*”“market*”). Papers were retrieved for 2000–2023 years. Peer-reviewed literature was complemented by papers and documentsretrieved from the gray literature.The subsequent sections of the study are organized as follows.The first section presents the characteristics of PDMPs and theirmain indications. The second discusses the demand, supply,regulation, and self-sufficiency of the PDMP market and itsdifferences from other medicines. The third section highlights theshortcomings and possible solutions to the existing challenges.Plasma-derived medicinal products:characteristics and therapeutic indicationsPDMPs are produced using industrial plasma manufacturingprocesses. Plasma is a blood component originating from thevoluntary donation of biological material by donors, which isconducted according to two models: a) the public model, forexample, in Italy, where the donation is voluntary and unpaid, orb) the private model, such as in the United States, where thedonation is voluntary and paid.Plasma is not only used for the industrial production of bloodproducts but also in the healthcare sector as a blood component,although its clinical indications are becoming increasingly restrictive.The production of PDMPs is particularly complex, highlystandardized, and regulated. Donated plasma is collected either inpublic transfusion departments or in specialized centers (includedthose of the pharmaceutical companies) with expertise in bloodseparation and plasmapheresis (a technique used to separate plasmafrom the remaining blood components that are immediately re-infused into the original donor). The production process comprisesseveral phases. The first is fractionation, which is a chemical-physical process aimed at separating plasma proteins (albumin,immunoglobulins, coagulation factors, and other proteins ofinterest in some rare diseases). The following production phasesremove and inactivate potentially dangerous microorganisms,involving purification, viral inactivation/removal, and asepticfilling or freeze-drying. At the end of these processes andcontrols, the drug is considered safe for packaging andsubsequent distribution to the patients. Thereafter, the safety isconstantly monitored through pharmacovigilance.PDMPs are indicated for the treatment of several severe diseasesand, in some cases, in particular as regards as immunoglobulins(IGs), cannot be replaced by other products for the treatment ofacute and chronic clinical conditions.The strategic and pivotal role of PDMPs has been confirmed bythe inclusion of IGs and coagulation factors (VIII and IX) in the listof drugs considered essential for basic healthcare services by theWorld Health Organization (World Health Organization, 2021).The most commonly used PDMPs in clinical settings and theinternational market are as follows:➢Albumin—used for treating liver cirrhosis and its complications,aimed at increasing the general oncotic pressure. It is also necessaryto treat hypovolemic and septic shock, burns, severe neonataljaundice, and nephrotic or malabsorption syndromes.➢ Coagulation factors (VII, VIII, IX, X, and von Willebrand) arerequired to treat coagulation diseases and disorders, such ashemophilia A and B, von Willebrand disease, and clottingfactor deficiency due to liver diseases.➢ Specific IGs are necessary to prevent the development ofhepatitis B, tetanus, cytomegalovirus infections, maternal-fetal Rh factor incompatibility, and immunomodulation inorgan transplants.➢ Polyvalent immunoglobulins are necessary for prophylaxis againstinfections in patients with primary or secondaryimmunodeficiencies and in certain neurological pathologies(chronic inflammatory demyelinating polyradiculoneuropathy,multifocal motor neuropathy, or Guillain–Barré syndrome).➢ Antithrombin III, a drug used to treat congenital or acquiredantithrombin III deficiencies.➢ Prothrombin complex concentrate is used for the treatmentand prophylaxis of bleeding episodes.➢ Fibrinogen, a drug used for the treatment of congenital oracquired deficiency of this specific factor andhemorrhagic disorders.➢ Alpha1-proteinase inhibitor, a drug used to treat alpha1-antitrypsin deficiency.➢ C1-esterase inhibitor, which is used to treat the clinicalmanifestations of hereditary angioedema.The use of IGs deserves particular attention (Prevot and Jolles,2020). As discussed below, there has been a consistent increasein their use.IGs are available as sterile preparations of concentratedantibodies extracted from the plasma for subcutaneous orintravenous administration.The primary established indications for intravenouslyadministered IGs are as follows (Kivity et al., 2010; Perezet al., 2017):➢Primary immunodeficiency syndromes with impaired antibodyproduction.➢ Secondary immunodeficiencies in patients with severe orrecurrent infections, ineffective antimicrobial treatment, andinability to produce specific antibodies.➢ Immunomodulation in adults, children and adolescents for:o Primary Immune Thrombocytopenia in patients at high riskof bleeding or before surgery to restore platelet count.o Guillain–Barré syndrome.o Kawasaki disease (in conjunction with acetylsalicylic acid).o Chronic inflammatory demyelinating polyneuropathy.o Multifocal motor neuropathy.Frontiers in Pharmacology frontiersin.org02Bolcato and Jommi 10.3389/fphar.2024.1375891Intravenously administered immunoglobulins are alsocommonly used drugs for the following clinical indications:➢ Myasthenic crisis.➢ Rapid worsening forms of myasthenia gravis and diseaseexacerbation when a rapid improvement in musclestrength is required to minimize the risk of bulbar palsy orrespiratory failure.➢ In the initial stages of myasthenia gravis, when the effects ofcortisone and/or immunosuppressive therapy are anticipated.➢ As preparation for thymectomy, in patients withmyasthenia gravis.➢ Patients with myasthenia gravis who are unresponsive tosteroid and/or immunosuppressive drug therapies or havecontraindications to their use.Subcutaneously administered immunoglobulins are licensed forthe following:➢ Primary immunodeficiency syndromes with impairedantibody production.➢ Hypogammaglobulinemia and recurrent bacterial infectionsin patients with chronic lymphocytic leukemia, who do notrespond to antibiotic prophylaxis or in whom antibioticprophylaxis is contraindicated.➢ Hypogammaglobulinemia and recurrent bacterial infectionsin patients with multiple myeloma.➢ Hypogammaglobulinemia in patients undergoing allogeneichematopoietic stem cell transplantation.Administration of IGs is considered life-saving in many of thesepathological conditions. The medical need for IGs has grown rapidlydue to several factors (Kerr et al., 2014; Farrugia, 2021; HoganLovells, 2022; Quinn et al., 2022): a) general aging of the population,which is potentially more in need of treatment and medicines; b)patients with an indication for the administration of IGs who, thanksto the effectiveness of this treatment, have a longer life expectancy,thus making a correspondingly longer therapy need; c) increaseddiagnosis rates of diseases that can benefit from the administrationof IGs thanks to scientific progress and the possibility of carrying outmore accurate (even genetic) diagnoses; d) identification of newtherapeutic indications for IGs as a common side effect of newtreatments, such as immunotherapy in oncology, resulting insecondary immunodeficiency and immune-mediated neurologicaland rheumatological diseases.Market dynamics: PDMPs vs.other medicinesMarket dynamics depend on the demand (consumers) andsupply (producers). The demand for any product (good orservice) is affected by the need for and perceived value of theproduct compared to existing alternatives, relative price, andavailable budget. Producers are generally driven by profitmaximization, that is, by maximizing the difference betweenrevenue and cost. Free interaction between demand and supplyenables the efficient allocation of resources, optimizing thesatisfaction of needs with the available resources if the demandand supply are separated from each other and fully informed, if theconsumers are rational (the price they are able to pay reflects thevalue of the product), and the suppliers are sufficiently numerous togenerate competitive pricing. Otherwise, the market should not beleft to the free interaction between demand and supply, but shouldbe regulated. Generally, the healthcare sector is affected by marketfailures, including monopolies generated by patent protection,limited information, and physicians who simultaneously demandhealthcare for their patients and supply healthcare services, with therisk that they are not perfect agents in the way they demandhealthcare on behalf of their patients. For this reason, healthcaremarkets are often regulated. For example, the industry is not free toset prices because it can exploit monopolistic power, imposing a veryhigh economic burden on consumers. Furthermore, marketmechanisms are based on price discrimination: demand isaffected not only by consumers’ willingness but also by theirability to pay, which depends on budget constraints. Pricediscrimination is generally not acceptable in the healthcaresector, and third-party payers—namely, the government, socialinsurance, and private insurance—cover healthcare costs,collecting resources through taxes, payroll taxes, and insurancepremiums, respectively.Market regulation implies that domains that would not havebeen considered by demand (need, comparative value, and budgetconstraints) and supply (costs and revenues) are mediated byregulators. The existence of third-party payers may drive demandwell beyond the level that would have been reached if patientsthemselves had to pay. Prioritization, guidelines, and, for someproducts, copayments (i.e., a partial reintroduction of prices) can beused to govern the demand for healthcare.On this aspect, PDMPs are similar to other medicines. Patients’need depends on disease severity, that is, the prognosis (lifeexpectancy), quality of life, and economic burden of the disease.It has been demonstrated, for example, that hemophilia, which isone of the target of PDMPs, generates an average 0.69 utility score,where utility is an indicator of Health-related Quality of Life (HR-QoL) ranging from 0 (death/vegetative state) to one (perfect health),severe hemophilia produces 0.197 Disability Adjusted Life Years,i.e., 20% years lost because of premature death or disability(compared to 12% for diabetes, 16.7% for major depression(Kluszczynski et al., 2020). The economic burden of hemophiliain Europe ranged from €67 k in Spain to €195 k in Germany(Cavazza et al., 2016).The comparative value depends on the added therapeutic value(impact on survival and HR-QoL and/or endpoint surrogating finaloutcomes) and other value domains, including patient preferences(e.g., better administration route) and the impact on the healthcareorganization (e.g., oral vs. intravenous administration). Pricenegotiation is generally more focused on added therapeutic value;the larger the added therapeutic value, the higher the premium pricewith respect to comparators (Vogler et al., 2017). Value domains canbe more discretionally included in value-for-money considerationsor embedded into specific indicators such as the incremental cost-effectiveness ratio (Jommi et al., 2020). Regardless of the methodused to convert the value into an acceptable price, the time horizonof the evaluation and the perspective used to estimate avoidable costsmay have an important impact on the value for money. The longerFrontiers in Pharmacology frontiersin.org03Bolcato and Jommi 10.3389/fphar.2024.1375891the time horizon and broader the perspective used, the higher theprobability of appreciating the full impact of a new medicine.In their price requests, the industry (supply side) considersrevenues and costs. The former depends on prices and volumes;the smaller the expected volumes (e.g., medicines for rare diseases,which are the target for many PDMPs) (Strengers, 2023), the higherthe price request. The costs depend on the unit prices and quantity ofinput used (personnel, consumables, services, equipment, etc.) forresearch and development (R&D), production, selling, and generaland administrative expenses. In this respect, PDMPs share withother medicines the peculiarity of high R&D costs, including jointand sunk costs.Unlike most other medicines and particular drugs derivedfrom chemical synthesis, PDMPs are characterized, as previouslymentioned, by a complex, long, and expensive productionprocess. It has been estimated that the time required to movefrom plasma donation to treatment administration can be as longas 7–12 months (Farrugia and Scaramuccia, 2017) and themanufacturing costs (including plasma as raw material)account for 57% of the total costs of PDMPs, compared to14% for small molecules (Grabowski and Manning, 2018). Thelatter estimates refer to US production costs which are affected bydonor fees, but, since US is the largest producer and exporter ofPDMPs, they affect the production costs of PDMPs usedworldwide in general. Another characteristic of the productionprocess is its rigidity. Due to the long lead times, unexpectedincreases in clinical need cannot be addressed in the short term,and diverse sources of plasma should be used, as possibleshortages in the availability of blood in one country could becompensated for by others.Another peculiarity of PDMPs is the joint nature of theirplasma samples. Fractioned plasma is used for different PDMPs,which are indicated for different diseases with differentprevalence. Once the demand for very rare diseases has beensatisfied, the collection and fractionation of plasma will serve theproduction of PDMPs targeting only patients suffering fromdiseases with a higher prevalence, making the marginal(additional) revenue lower, while the marginal (additional)cost remains constant. The industry will continue to produceuntil the marginal revenue is higher than the marginal cost ofproducing 1 L and stops producing when the marginal revenueequals the marginal cost (last liter economics). The last litereconomics reduces the convenience of producing PDMPs that areused for larger patient population, such as albumin and IGs(Kluszczynski et al., 2020).Plasma and self-sufficiencyThe production of PDMP, for which recombinant factorproducts are not available, depends on plasma collection. TheWHO has recommended self-sufficiency in safe blood and bloodproducts based on voluntary non-remunerated donations (WHOExpert Group, 2012), but the achievability of this goal has beenquestioned (Flanagan, 2014; Farrugia and Scaramuccia, 2017). Infact, few countries have reached self-sufficiency in plasma (Rocket al., 2000) and must rely on an open market. Europe imported 38%of its plasma need for fractionation and is reliant on plasma importsfrom the US (Haanperä et al., 2021). In 2019, North America(mainly the US) accounted for 67% of plasma fractionation, thatis, it is the main source of PDMPs used commercially; 18% of theplasma sourced comes from the Asia-Pacific region, of which 75%from China; the contribution of Europe is 14%, although Europe isthe largest supplier of recovered plasma (Strengers, 2023). Thisscenario makes supply extremely sensitive to increases in plasmacollection costs in the US.On July 2022, a proposal for a regulation on substances ofhuman origin (SoHO) for human application was published by theEuropean Commission. To date, it is in the legislative process andpresumably will replace the largely outdated legislation on Blood,Tissue and Cells (BTC legislation). Thanks to this regulation, theEuropean Parliament will put in place a number of positive actionsthat can help improve plasma availability in Europe (The EuropeanParliament and the Council, 2022).Italy implemented a plasma self-sufficiency program under Law219/2005. According to this program, blood is collected through thepublic system (blood centers of the Italian National Health Service -INHS) and owned by the Regions. PDMPs are produced by theindustry on behalf of the INHS, based on agreements with theRegions or Regional networks (Lanzoni et al., 2013). If the PDMPsvolume coming from the national blood system is insufficient, theINHS can buy it from the open market. The pharmaceuticalcompanies indeed can collect plasma in countries where itscommercial use is allowed to obtain products that can be sold onthe open market (after price negotiation with national authorities)(United States, Austria, the Czech Republic, Germany, Hungary,Ukraine, and China) (Strengers, 2023). In 2021, PDMPs producedvia a self-sufficiency program in Italy covered 71% of the demand,ranging from 10% for subcutaneous IGs (82% for intravenous IGs)to 100% for Factor VIII (Candura et al., 2023).PDMPs’ shortageThe shortage of PDMPs, particularly IGs, is a consequence ofhigher demand-over-supply. This was also previously observed. Forexample, in the fall of 1997, a shortage of intravenousimmunoglobulin occurred in the US because of the recall ofsome products, and although the shortage was spontaneouslyovercome, a more proactive intervention of regulators wasadvocated for future emergencies (Boulis et al., 2002).On the one hand, supply issues include risk of deviation andnon-excellent planning of consumption. IGs supply difficulties,become even worse during the pandemic period, have negativelyaffected plasma collection (Hartmann and Klein, 2020; Covingtonet al., 2022). In the US, plasma collection decreased by 18% in 2020.Worldwide, this decline amounted to 14.5% (Strengers, 2023). InItaly, after a decrease in 2020 (−1.7%), volumes of plasma increasedby 2% in 2021. Despite a partial recovery, the 2021 increase waslower than the average growth rate of previous years (Candura et al.,2023), making it more difficult to achieve self-sufficiency. Asexpected, the decrease in the supply of plasma increases its cost.The cost per liter of plasma has increased by 59.3% in Europe and40.7% in the United States between 2017 and 2022, moving from€108 to €172 in Europe and from $162 to $228 in the United States(Marketing Research Bureau, 2020). In the last 5 years, donor feesFrontiers in Pharmacology frontiersin.org04Bolcato and Jommi 10.3389/fphar.2024.1375891have increased by 30% in the US to better compensate donors andcounteract the decrease in plasma collection (Brown, 2020; Bernini,2021). An increase in the cost of plasma has impacted thesustainability of PDMP production. During the pandemic period,in Italy IGs have been particularly affected by shortages, which havealso caused rationing in the case of diseases for which they have beenprioritized (AIFA, 2022). Even in countries with a high supply ofcommercially-sourced plasma (like Germany and the US), shortagesof intravenous/subcutaneous IGs have occurred (Strengers, 2023).The demand for PDMPs has increased over time. This increaseis motivated not only by the availability of new products or newindications for existing PDMPs but also by higher dosages toenhance PDMP effectiveness (Kluszczynski and Barbosa Eitel,2022). This demand is expected to increase in the future,considering the diagnostic gaps that are required to be filled(Strengers, 2023). This increase is particularly significant for IGsglobally (Farrugia et al., 2019) and their demand is expected to riseby 30% by 2030 (CSL Behring, 2022; Kluszczynski and Barbosa Eitel,2022). In Italy, despite efforts to fulfill this demand with the self-sufficiency program (Farrugia et al., 2019), a large proportion is stillnot covered (36% for IGs in 2021) (Candura et al., 2023).The supply/demand gap: what policiesshould be implemented?Policies aimed at reducing the imbalance between the supplyand demand should address the right target.An excess of the demand over the supply can be addressed bytwo possible actions. If the demand is inappropriate, it should bereduced. If the demand is appropriate but the supply cannot beincreased, the demand should be prioritized to the highest unmetneed; for example, for patients for whom PDMPs are the onlyavailable treatment. The two options seem interconnected and thedebate on clinical use, and particularly on the evidence supportingoff-label use, is still controversial (Farrugia and Poulis, 2001; Brandet al., 2021; Kluszczynski and Barbosa Eitel, 2022; Strengers, 2023).As a consequence of the pandemic, prioritization programs forIG use have been implemented in Italy (AIFA, 2022) and otherWestern Countries (ANSM, 2018; Whittington Health NHS, 2018;Canadian Blood Services and National Advisory Committee onBlood and Blood Products, 2020).The guidance document prepared in Italy by AIFA (AgenziaItaliana del Farmaco - Italian Medicines Agency) and the NationalBlood Center includes prioritization guidelines for IGs similar tothose of the Canadian Blood Services and National AdvisoryCommittee on Blood and Blood Products (Canadian BloodServices and National Advisory Committee on Blood and BloodProducts, 2020), and containment guidance for their use in specifictherapeutic areas depending on the availability of the products.Although it appears necessary and useful to minimize theconsequences caused by IG shortages and to call for rigor intheir administration, this model appears to be a new obligatorymodel of distributive justice. In fact, it may generate, depending onthe situation, different IG prescriptions and usage behaviors forpatients in different regions. This extremely complex situation hasnever occurred in many respects and risks not allowing the fullapplication of the principles on which a public health system isbased, as it should ensure universality and equal access for equalhealth needs. This can lead to social imbalances and medicolegalrisks in the event of difficulty in accessing appropriate andnecessary care.The supply shortage can be addressed through threepossible actions.The first is an increase in plasma collection. This is not easy toimplement because, the determinants of plasma donation may varya lot. Major motivations of blood donors, new or regular, appearrelated to the prosocial nature of donation (i.e., altruism,communitarianism, etc.), to personal values (i.e., moral norms),and to the comfort of the donation environment. It was also recalledthe importance of personal gain as a motivation for the firstdonation (going from personal satisfaction to taking time ontheir work hours) (Beurel et al., 2017). Furthermore, the currentsupply of plasma suffers from specific contingencies, includingmilitary conflicts (the war in Ukraine and the plasma supply inUkraine) and newly emerging pathogens (SARS-CoV-2) (Strengers,2023). Plasma collection could be particularly critical in systems thatrely on voluntary unpaid plasma collection; donor management isexperiencing and will experience important challenges due todemographic changes and, in some countries, competingcommercial and remunerated activities (De Kort, 2010). Forexample, in Italy, by law (Ministero della Salute, 2015) onlyhealthy individuals aged between 18 and 65 years may donateand, in rare cases, this age can be increased to 67–68 years, basedon the physician’s discretion. According to demographic projectionsby the Italian National Institute of Statistics (ISTAT), the residentItalian population will significantly decline, and according toestimates from ISTAT (ISTAT, 2018), in 2030 the average age ofthe Italian population will be > 50 years. In addition, around one-third of the total population will be ≥ 65 years of age. Consequently,the population potentially eligible for donation will decrease,whereas the number of those potentially requiring PDMPswill increase.Increasing plasma collection may not be decisive becausecompanies will suffer from the impact of the last liter economics.Shortage particularly affects the sustainability of IGs because plasmacollection costs result in decreasing marginal revenue (last litereconomics). Notwithstanding, actions have been taken bypharmaceutical companies, such as increasing the number ofcenters, improving production efficiency, and improvingaccessibility of plasma collection centers.Some initiatives have also been implemented at the Europeanlevel (Brand et al., 2021), regarding plasma collection, such as the“Supply” Program, aimed at identifying the best practice,formulating recommendations to disseminate and harmonizeit, ensuring an increase in plasma collection by transfusionservices, and formulating a proposal for a common Europeanpolicy capable of mitigating the effects of the decrease in plasmaavailability with the consequent increase in dependence on non-European countries.The third action is to enhance the technical efficiency of theproduction process, thus increasing the yield per liter of the collectedplasma. In the last 10 years, there has been a significant commitmentby pharmaceutical companies to improve production efficiency andincrease fractioning capacity, also benefiting the public system (DeAngelis et al., 2019; Farrugia et al., 2019). Additionally, moving fromFrontiers in Pharmacology frontiersin.org05Bolcato and Jommi 10.3389/fphar.2024.1375891a monopolistic to a competitive tender system for the production ofPDMPs on behalf of the INHS led to an increase in the yield per literof fractionated plasma (De Angelis and Breda, 2019). However,some publications have highlighted that there remains room forgreater efficiency, for example, standardizing the production costs ofPDMPs obtained from national plasma, which exhibits hugevariability among blood establishments, and improving theefficiency of plasma collection (Grazzini et al., 2013).If the shortage is diffused and generated by a general increase inthe cost of raw materials, as is the case for plasma, and if this costincrease is not sustainable and generates losses, the solution could beto increase the price of PDMPs, especially IG. A price increasereduces the losses of the last liter of plasma collected.The shortage could also be motivated, at the local level, by lowerprices compared to those of other countries or unfavorableregulations that align prices with other countries but lower actualrevenues (e.g., clawback systems). Since the cost of plasma collectionmay no longer be sustainable, companies may allocate scarceproducts to the most remunerative markets once prioritizedunmet needs have been satisfied, and direct or indirect increasesin prices would make more attractive markets where low pricescannot be afforded by pharmaceutical companies.An increase in the price of IG was awarded to pharmaceuticalcompanies in Germany and the Nordic Countries. In Italy, a priceincrease could be granted if the cost of raw materials increases(AIFA, 2020) and it has been recognized by AIFA.Regarding clawbacks/paybacks, there is evidence that this policyhas a negative effect on PDMP availability. In Italy, there is a dualpayback regulation that is applied to PDMPs procured in the openmarket and not applied to PDMPs produced on behalf of the INHS.Extending the payback exemption to all PDMPs would make Italymore attractive to companies that produce commercial PDMPs andthereby reduce shortages in Italy.The last policy which is worth mentioning is improvingallocative efficiency from the supply and demand side, that isoptimizing the use of plasma reallocating it from clinical useto PDMPs.The increase in plasma collection can be particularly addressedto plasmapheresis, which ensures a greater frequency of collection.According to Italian law, for example, plasmapheresis may beperformed up to 12 times per year, unlike the donation of wholeblood or red blood cells, which may be performed up to four timesper year. In Italy, often plasma donation is not deemed to be asimportant as red blood cell donation. Conversely, it is necessary toupdate this outdated vision and mention the current standard ofcare in transfusion medicine, which is represented by Patient BloodManagement, defined as “a patient-centered, systematic, evidence-based approach to improve patient outcomes by managing andpreserving a patient’s own blood, while promoting patient safety andempowerment” (Shander et al., 2022).The approach involves timely and multidisciplinary applicationof evidence-based medical and surgical concepts aimed at (1)detecting early and treating anemia appropriately, (2) minimizingsurgical, procedural, and iatrogenic blood loss and managingcoagulopathic bleeding in the care setting, and (3) supporting thepatient when treated with the most appropriate therapy. Thissystematic and multimodal approach has been shown to beeffective in reducing the number and the volume of red bloodcell transfusions, thereby enabling the successful execution ofcomplex interventions without the use of blood components(Shander et al., 2016; Costanzo et al., 2020). In addition, it hasalso led to a decrease in negative outcomes, such as mortality,morbidity, healthcare-associated infections, and costs (Leahyet al., 2017). The program has also been demonstrated to reducethe risk of medico-legal disputes arising from transfusionadministration (Bolcato et al., 2020). Accumulating scientificevidence about the results of the program shows that several redblood cell transfusions may be avoided making them less necessary,rather than becoming the last expendable resource at the end of acomplex process. Conversely, there are no similar possibilities oralternative strategies in case of need for life-saving blood products.Therefore, institutions and healthcare stakeholders shouldincreasingly encourage the shift towards the “yellow donation”(plasma donation). This approach should be cultivated from asocial perspective by educating and training donors tounderstand the current needs in the transfusion world. PatientBlood Management could play a central role in increasing theproduction of PDMPs, decreasing the clinical use of plasma, andconsequently increasing its contribution to plasma derivation.Currently (Liumbruno et al., 2009; Roback et al., 2010; Greenet al., 2018), the indications for the clinical use of plasma areextremely limited; they are associated with rare situations, suchas hemolytic purpura or other microangiopathies, and thecorrection of coagulation deficiencies when specific coagulationfactors are not available. In the latter case, it should behighlighted that several coagulation factors are marketed that arehighly effective, thereby reducing the need for plasmaadministration (which may result in several transfusion risks andissues). Consequently, the indications for plasma transfusion arelimited. Despite this, at least in Italy, it is used in a massive andinappropriate manner to increase the circulating fluid mass orreverse the effects of anticoagulants (Desborough and Stanworth,2013; Chai-Adisaksopha et al., 2016). This ineffective use of plasmainvolves its subtraction from plasmapheresis activities, and showsthe need for a broad educational intervention on the transfusionappropriateness of this blood component. A virtuous experiencereported in the literature shows the results of a “zero tolerance”policy on the use of this blood component (Beverina et al., 2019).This led to a >70% reduction in the use of plasma compared to theprevious 5 years thereby facilitating a substantial increase in thevolume of plasma supplied for industrial processing (Beverinaet al., 2019).ConclusionThe shortage of PDMPs, particularly IGs, is an important publichealth issue. Despite the pandemic exacerbating this problem andhaving a considerable negative impact on plasma collection volumesand costs, it is likely that the shortage will persist in the future. Theincreasing costs of plasma and the last liter economics could make itunsustainable for pharmaceutical companies to producemore PDMPs.Ethical considerations and market regulations should be thedrivers of any policy aimed at addressing an imbalance between thedemand and supply of PDMPs and the consequent PDMP shortage.Frontiers in Pharmacology frontiersin.org06Bolcato and Jommi 10.3389/fphar.2024.1375891This would start from a recognition that self-sufficiency veryunlikely will fully satisfy the demand for PDMP and should beintegrated with commercial PDMP.A broader vision of the causes of this shortage could providesolutions in the short- and long-term. An appropriate planning iscrucial, considering that the supply is quite rigid and does notimmediately respond to a demand increase.Improving technical and allocative efficiency and providingincentives to all stakeholders in the PDMP market should bepursued. Technical efficiency refers to an increase in the ratiobetween output (PDMPs) and input (plasma). Allocativeefficiency refers to both the production aspect (e.g., reducing therole of plasma in clinical practice and relying more onplasmapheresis) and the demand aspect (e.g., making thedemand more appropriate and addressing the use of PMPDs toeffectively prioritize needs). Incentives to all stakeholders mayinclude indirect ones for donors and higher prices and/or betterregulation (e.g., no clawbacks/paybacks) for PDMPs to compensatefor the rising plasma costs and the decreasing marginal revenuegenerated by an additional unit of plasma per liter (last litereconomics). There are several factors to be considered inaddressing this public health challenge, which should inspireconcerted actions based on a broad vision that prompts allstakeholders, both public and private, to adopt decisive action.Author contributionsMB: Conceptualization, Data curation, Formal analysis,investigation, Methodology, Project administration, Validation,Writing–original draft, Writing–review and editing. CJ:Conceptualization, Data curation, Formal Analysis, Investigation,Methodology, Supervision, Validation, Writing–original draft,Writing–review and editing.FundingThe author(s) declare financial support was received for theresearch, authorship, and/or publication of this article. The authorsdeclare that this study received funding from CSL Behring. Thefunder was not involved in the study design, collection, analysis,interpretation of data, the writing of this article, or the decision tosubmit it for publication.AcknowledgmentsWe acknowledge SEEd Medical Publishers, which performedjournal styling services and English language editing. These serviceswere funded by CSL Behring.Conflict of interestMB reported serving as an advisory board member and a paidspeaker for CSL Vifor and CSL Behring, outside the submitted work.CJ reported serving as an advisory board member and a paid speakerfor Amgen, AstraZeneca, BMS, CSL Behring, Gilead, Incyte, MSD,Roche, Sanofi, Takeda.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. 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